Fusobacterium nucleatum interacts with cancer-associated fibroblasts to promote colorectal cancer

Abstract

Fusobacterium nucleatum; Cancer-associated fibroblasts; Colorectal Cancer

Fusobacterium nucleatum; Fibroblasts associats al càncer; Càncer colorectal

Fusobacterium nucleatum; Fibroblastos asociados al cáncer; Cáncer colorrectal

Gut microbial species contribute to colorectal cancer (CRC) by interacting with tumor or immune cells, however if CRC-associated bacteria engage with stromal components of the tumor microenvironment remains unclear. Here, we report interaction between the CRC-associated bacterium Fusobacterium nucleatum and cancer-associated fibroblasts (CAFs), and show that F. nucleatum is present in the stromal compartment in murine CRC models in vivo and can attach to and invade CAFs. F. nucleatum-exposed CAFs exhibit a pronounced inflammatory-CAF (iCAF) phenotype, marked by elevated expression of established iCAF markers, secretion of pro-inflammatory cytokines such as CXCL1, IL-6 and IL-8, generation of reactive oxygen species (ROS), and an increased metabolic activity. In co-culture experiments, the interaction of cancer cells with F. nucleatum-stimulated CAFs enhances invasion, a finding further validated in vivo. Altogether, our results point to a role for the tumor microbiome in CRC progression by remodeling the tumor microenvironment through its influence on cancer-associated fibroblasts, suggesting novel therapeutic strategies for targeting CRC.

This work was supported by the Luxembourg National Research Fund [CORE/C16/BM/11282028 (EL), CORE/C15/BM/10404093 (PW), PoC/18/12554295 (EL), CORE/C21/BM/15718879 (JM), AFR 17103240 (CG), PRIDE Doctoral Research in the scope of the Doctoral Teaching Unit - MICROH PRIDE17/11823097 to MT, and CANBIO PRIDE21/16763386 (CCTB). The study was further supported by the FNR and the Fondation Cancer Luxembourg grant CORE/C20/BM/14591557 (to EL), an FNR matched funding schemes (MFP20/15251414/MelCol PFP, EL), an Internal Research Project at the University of Luxembourg (MiDiCa; EL, PW, SH) as well as an FNRS-Télévie funding scheme 7.4565.21 and 7.6603.02 to MM, 7.4560.22 to PS and 7.4552.23 to MG, by the Fondation du Pélican de Mie and Pierre Hippert-Faber under the aegis of the Fondation de Luxembourg (JK, MM, DT, and MT), the Fondation Schumacher (EL), a postdoctoral fellowship from the Swiss National Science Foundation (P500PB_214405, PPE), a postdoctoral fellowship from the Spanish Fundacion Ramon Areces (JAMT), the Fondation Gustave et Simone Prévot (EL). We would like to thank the Fondation Cancer and the University of Luxembourg for their support of the Luxembourgish CRC patient cohort. JV received relevant funding from Deutsche Forschungsgemeinschaft (DFG; SFB 1583/1 DECIDE, Project number: 492620490, Subproject A09). Moreover, this work was supported by Cancer Research UK [grant number C17937/A29070], Fondo de Investigaciones Sanitarias (FIS) grant (PI20/00889) from the Instituto de Salud Carlos III (ISCIII) and Fundación Mutua Madrileña (MMADRILEÑA/PREMI/2020CCAA_NUCIFORO). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.